Bryostatin 1 is a macrocyclic lactone protein kinase C (PKC) activator that has recently undergone phase I evaluation in humans. Preclinical evidence indicates that bryostatin 1 increases the susceptibility of human leukemic cells to 1-beta-D-arabinofuranosylcytosine (ara-C)- induced apoptosis in a dose- and schedule-dependent manner, and that this phenomenon is associated with bryostatin 1-mediated :PKC down- regulation. In vivo administration of bryostatin 1 has been shown to down-regulate splenocyte PKC activity in a murine model. Moreover, in a recently completed phase Ib pharmacodynamic trial in humans, a fixed dose of bryostatin 1 (25 g/M2) administered according to three schedules was observed to induce down-regulation of peripheral blood mononuclear cell PKC activity in a subset of patients. Based upon these findings, a phase I trial has been designed and subsequently approved by CTEP in which escalating doses of bryostatin 1 will be administered before and after high-dose ara-C (HIDAC) in patients with refractory leukemia. The goals of this trial are (1) to identify the MTD of bryostatin 1 administered as a 24-hour infusion immediately before and after 4 courses of HIDAC (1.5 gM/M2 q hx4 on days 1+2 and 9+10); (2) to identify the dose-limiting toxicities of this regimen; (3) to assess the effects of bryostatin 1 on HIDAC pharmacokinetics, and (4) to determine, using a platelet aggregation-based bioassay, whether escalation of the bryostatin 1 dose will lead to detectable plasma levels. Funds are now requested for clinical and data management support for this clinical trial, as well as correlative pharmacokinetic studies. It is anticipated that this trial could serve as a prototype for future studies in which agents acting through signal transduction pathways are combined with conventional cytotoxic agents in the treatment of patients with refractory hematopoietic and other malignancies.